Aim: Gastric cancer is a major health problem and current treatment lacks lasting effect. Targeted therapy for gastric cancer with specific genetic background is in urgent need.
Methods: We have studied The Cancer Genomic Atlas (TCGA) and The Genomics of Drug Sensitivity in Cancer (GDSC) databases to reveal genes with high frequency of mutation and possible sensitive compound against such gene mutation. In vitro studies were conducted to validate the in silico findings.
Results: CDKN2A is frequently mutated in gastric cancer, revealed in TCGA database. CDK4/6 inhibitor PD-0332991 was sensitive in cancer cells with CDKN2A mutation, revealed in GDSC database. In vitro studies showed that PD-0332991 could selectively inhibit proliferation of gastric cancer cell with CDKN2A mutation. PD-0332991 could also inhibit cell invasion, migration, and colony formation of gastric cancer cell with CDKN2A mutation. PD-0332991 induced cell cycle arrest but not apoptosis. PD-0332991 inhibited xenograft gastric cancer mouse model.
Conclusion: Gastric cancer with CDKN2A mutation is sensitive to CDK4/6 inhibitor. PD-0332991 is a potential therapeutic agent for gastric cancer.
Keywords: CDK4/6; CDKN2A; Gastric cancer; cell cycle.